TWiV 337: Steamer

On episode #337 of the science show This Week in Virology, Vincent meets up with Michael and Steve to discuss their finding of a transmissible tumor in soft-shell clams associated with a retrovirus-like element in the clam genome.

You can find TWiV #337 at www.microbe.tv/twiv.

A transmissible cancer of soft-shell clams

Mya_arenariaA leukemia-like cancer is killing soft-shell clams along the east coast of North America. The cancer is transmitted between animals in the ocean, and appears to have originated in a single clam as recently as 40 years ago.

Hemic neoplasm is a disease of marine bivalves that is characterized by proliferation of morphologically and functionally aberrant hemocytes, the cells that circulate in the circulatory fluid of mollusks. A newly identified LTR retrotransposon called Steamer correlates with neoplastic disease in clams. LTR retrotransposons are DNA sequences in the genome that are thought to be precursors to retroviruses. The normal clam genome contains 10-20 copies of Steamer, compared with 150-300 copies in neoplastic hemocytes.

Integration of retroviruses into the genome is a known mechanism for disrupting cellular growth control, leading to uncontrolled proliferation and ultimately development of cancer. Whether Steamer causes neoplasia, by integrating near an oncogene, can be determined based on where this retroelement has inserted in the clam genome.

Analysis of 12 Steamer integration sites revealed that 7 were present in neoplastic samples from clams collected at sites in New York, Maine, and Prince Edward Island, Canada. Examination of nuclear and mitochondrial DNA revealed that cancerous hemocytes collected from clams at all three sites contain similar mutations that are not present in normal tissues. These observations indicate that these neoplasms  are nearly genetically identical and could not have arisen from the hosts. The cancer probably originated in a single clam and was then transmitted to other animals.

Cells from different vertebrates are usually rejected by the host immune system, which recognizes foreign cells by the major histocompatibility (MHC) system. However, mollusks do not have MHC, which may explain why tumor cells can be transmitted among clams. Two other transmissible tumors have been described: the canine venereal tumor, which is sexually passed among dogs, and Tasmanian devil facial tumor disease, transmitted by biting. In both cases MHC molecules are low in tumor cells, explaining why they are not rejected by the recipient animal.

How cancer could spread among clams hundreds of miles apart is not known. Clams are filter feeders, which may lead to uptake of neoplastic cells released into the water by diseased animals. Movement of clams by humans might also have played a role in dissemination of disease along the northeastern US seaboard.

There are no known contagious human cancers, and it is unlikely that the steamer clam neoplasia could be transmitted to humans. It is not known how extensively hemic neoplasia will spread among soft-shell clams, or whether the disease could spread to other bivalves.

The Berlin patient

HIV binding CD4 and ccrSince the beginning of the AIDS epidemic, an estimated 75 million people have been infected with HIV. Only one person, Timothy Ray Brown, has ever been cured of infection.

Brown was diagnosed with HIV while living in Berlin in 1995, and was treated with anti-retroviral drugs for more than ten years. In 2007 he was diagnosed with acute myeloid leukemia. When the disease did not respond to chemotherapy, Brown underwent stem cell transplantation, which involves treatment with cytotoxic drugs and whole-body irradiation to destroy leukemic and immune cells, followed by administration of donor stem cells to restore the immune system. When his leukemia relapsed, Brown was subjected to a second stem cell transplant.

The entry of HIV-1 into lymphocytes requires two cellular proteins, the receptor CD4, and a co-receptor, either CXCR4 or CCR5. Individuals who carry a mutation in the gene encoding CCR5, called delta 32, are resistant to HIV-1 infection. This information prompted Brown’s Berlin physician to screen 62 individuals to identify a stem cell donor who carried a homozygous CCR5∆32 mutation. Peripheral blood stem cells from the same donor were used for both transplants. 

Despite enduring complications and undergoing two transplants, Brown’s treatment was a success: he was cured both of his leukemia and HIV infection. Even though he had stopped taking antiviral drugs, there was no evidence of the virus in his blood following his treatment, and his immune system gradually recovered. Follow-up studies in 2011, including biopsies from his brain, intestine, and other organs, showed no signs of HIV RNA or DNA, and also provided evidence for the replacement of long-lived host tissue cells with donor-derived cells. Today Brown remains HIV-1 free.

Although Brown’s cure is somewhat of a medical miracle, and by no means a practical road map for treating AIDS, the example of the Berlin patient has galvanized research efforts and continues to inspire hope that a simpler and more general cure for infection may someday be achieved. Clinical trials have been conducted to test a variety of strategies in which CD4+ T or stem cells are obtained from a patient, the CCR5 gene is either mutated or its translation blocked by RNA interference, and then the resulting virus-resistant cells are returned to the patient. In one case zinc finger nucleases were used to delete the CCR5 gene in a patient’s cells, a procedure that we discussed in TWiV #278.

TWiV 264: We should do an all-email show some day

On episode #264 of the science show This Week in Virology, the TWiVites read listener questions and comments about public engagement in science, vaccines, RNAi, reprogramming CD8 cells to treat cancer, rabies, and much more.

You can find TWiV #264 at www.microbe.tv/twiv.

Museum pelts help date the koala retrovirus

friendly-male-koalaThe genomes of most higher organisms contain sequences from retroviral genomes called endogenous retroviruses (ERVs). These are DNA copies of retroviral RNAs that are integrated into the germ line DNA of the host, and passed from parent to offspring. In most species the infections that lead to germ line ERVs appear to have occurred millions of years ago. The Koala retrovirus, KoRV, is the only retrovirus that we know of that is currently invading the germ line of its host species. A study of Koala pelts preserved in museums suggests how recently the virus infected this animal.

The koala is native to Australia, and all koalas in northern Australia are infected with KoRV. However not all animals in the southeast or on southern islands are infected. It is believed that KoRV crossed into koalas from another species (possibly the Asian mouse Mus caroli) some time within the past two hundred years. To test this hypothesis, DNA was extracted from 28 koala skins that were held in museums and which had been collected from the late 1800s to the 1980s. Polymerase chain reaction was used to detect KoRV DNA in the koala genome. The results show that KoRV was already widespread in Northern Australian koalas by the late 1800s. It has since spread slowly because the virus is not ubiquitous in southern koalas. The slow dispersal may due to the sedentary and solitary nature of koalas. Examination of mitochondrial DNA from the koala skins confirmed that there has been limited movement of the animals with Australia.

The sequence of the KoRV gene encoding the viral glycoprotein, env, was also determined. The results reveal that env sequences from museum specimens are remarkably similar to those of KoRV found in contemporary koalas. At first glance this result might not seem surprising: the endogenous KoRV genomes are evolving at the same slow rate as the host DNA into which they are integrated. However, there appear to have been multiple transmissions and germ line invasions by KoRV, leading the authors to suggest that in all cases very similar retroviruses were involved.

Infection with KoRV in captive animals is believed to cause immunosuppression, leading to fatal lymphomas or Chlamydia infection. A Chlamydia epidemic is believed to have killed many koalas in 1887-1889, consistent with the PCR results indicating that KoRV was widely present at that time.

Update: I had meant to discuss the possibility of dating the invasion of Koalas by KoRV by using older samples, but neglected to include this in the original article. Several days after it was published, Professor Paul Young sent me a note expressing exactly this sentiment:

What would be even better would be to have access to fossilised material that predates European settlement, that we could examine. We collaborated with an “Ancient DNA” specialist and tried this several years ago but we weren’t able to recover usable template DNA. Still worth some future effort though.

Avila-Arcos MC et al (2012). 120 years of koala retrovirus evolution determined from museum skins. Mol Biol Evol. 2012 Sep 14.